RAPID: Conserved Regions of the SARS-CoV-2 virus (COVID-19) RNA-RNA Interactions that Mediate Genome Dimerization and/or Progression Through the Viral Life Cycle

Mathematical and Physical Sciences - The genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), is encoded in RNA. This award funds studies by Drs. Mihaela-Rita Mihailescu and Jeffrey D. Evanseck at Duquesne University in to determine the structures and signals in the RNA that control the progression of the virus through various stages of its life cycle. Drs. Mihailescu and Evanseck use biophysical and computational methods to determine how structures of distantly separated parts of the RNA interact to switch from early stage protein production to late stage virus production. In addition, the project studies how conserved structures bring two separate RNAs together to allow parts to swap between genomes through a process called recombination. This recombination process provides an understanding for how the SARS-CoV-2 genome may have arisen from the exchange of genetic material among RNAs from viruses that infect different mammalian species. The impact of the project on society is to identify potential inhibitors against RNA-RNA interactions, which further provides leads for the development of therapeutic interventions against the SARS-CoV-2 virus and, correspondingly, stem the COVID-19 pandemic.

This goal of this study is to elucidate the molecular mechanisms controlling the progression of SARS-CoV-2 through essential steps of its life cycle and unravel a new, unexplored mechanism of RNA genomic dimerization that might facilitate its recombination. This research guides future development of new antivirals that target the genomic RNA of SARS-CoV-2 and potentially other similar RNA viruses. Bioinformatics and biophysical methods, including fluorescence spectroscopy, will be applied to elucidate the function of a highly conserved s2m RNA motif and to probe the long-range RNA-RNA interactions between the conserved sequences in the 5?- and 3?-untranslated regions (UTRs) of viral genes. The s2m RNA motif is proposed to form a ?kissing complex? intermediate that mediates dimerization of the SARS-CoV-2 RNA genome, thereby facilitating recombination events in coronaviruses and other additional viral families that share this motif. The UTRs are proposed to form "kissing interactions" that mediate the genome circularization, molecular switch that controls the transition between the translation and replication viral life cycle steps.

This grant is being awarded using funds made available by the Coronavirus Aid, Relief, and Economic Security (CARES) Act supplemental funds allocated to MPS.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.